Department of Cancer Prevention and Control and Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.
Department of Epidemiology, University of Florida, Gainesville, FL.
J Natl Cancer Inst. 2018 Jul 1;110(7):734-742. doi: 10.1093/jnci/djx260.
To what extent steroid hormones contribute to lung cancer in male and female never smokers and smokers is unclear. We examined expression of hormone receptors in lung tumors by sex and smoking.
Patients with primary non-small cell lung cancer were recruited into an Intergroup study in the United States and Canada, led by SWOG (S0424). Tumors from 813 cases (450 women and 363 men) were assayed using immunohistochemistry for estrogen receptor (ER)-α, ER-β, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Linear regression was used to examine differences in expression by sex and smoking status. Cox proportional hazard models were used to estimate survival associated with the receptors. All statistical tests were two-sided.
In ever smokers, postmenopause and oral contraceptive use were associated with lower nuclear ER-β (P = .02) and total (nuclear + cytoplasmic) PR expression (P = .02), respectively. Women had lower cytoplasmic ER-α (regression coefficient [β], or differences in H-scores = -15.8, P = .003) and nuclear ER-β (β = -12.8, P = .04) expression than men, adjusting for age, race, and smoking. Ever smokers had both higher cytoplasmic ER-α (β = 45.0, P < .001) and ER-β (β = 25.9, P < .001) but lower total PR (β = -42.1, P < .001) than never smokers. Higher cytoplasmic ER-α and ER-β were associated with worse survival (hazard ratio = 1.73, 95% confidence interval [CI] = 1.15 to 2.58, and HR = 1.59, 95% CI = 1.08 to 2.33, respectively; quartiles 4 vs 1).
Lower expression of nuclear ER-β in women supports the estrogen hypothesis in lung cancer etiology. Increasing cytoplasmic ER-α and ER-β and decreasing PR protein expression may be mechanisms whereby smoking disrupts hormone pathways.
类固醇激素在男性和女性不吸烟者和吸烟者中的肺癌发病机制中起多大作用尚不清楚。我们通过性别和吸烟情况检查了肺癌肿瘤中激素受体的表达。
美国和加拿大的 SWOG（S0424）领导的一项国际研究组招募了原发性非小细胞肺癌患者。对 813 例（450 例女性和 363 例男性）肿瘤标本进行了免疫组织化学检测，以检测雌激素受体（ER）-α、ER-β、孕激素受体（PR）和人表皮生长因子受体 2（HER2）。线性回归用于检验性别和吸烟状态表达的差异。Cox 比例风险模型用于估计与受体相关的生存情况。所有统计检验均为双侧检验。
在曾经吸烟者中，绝经后和口服避孕药的使用与核 ER-β（P =.02）和总（核+细胞质）PR 表达（P =.02）降低有关。女性的细胞质 ER-α（回归系数[β]或 H 评分差异= -15.8，P =.003）和核 ER-β（β = -12.8，P =.04）表达低于男性，调整年龄、种族和吸烟因素后。与从不吸烟者相比，曾经吸烟者的细胞质 ER-α（β= 45.0，P <.001）和 ER-β（β= 25.9，P <.001）均更高，而总 PR（β = -42.1，P <.001）更低。较高的细胞质 ER-α 和 ER-β 与更差的生存相关（风险比= 1.73，95%置信区间[CI] = 1.15 至 2.58，和 HR = 1.59，95% CI = 1.08 至 2.33，分别；四分位数 4 比 1）。
女性核 ER-β 表达降低支持雌激素在肺癌病因学中的假说。细胞质 ER-α 和 ER-β 增加和 PR 蛋白表达减少可能是吸烟破坏激素途径的机制。
